北京大學(xué)生命科學(xué)學(xué)院鄧宏魁研究組和北京大學(xué)定量生物學(xué)中心湯超研究組合作，首次證明小鼠體細(xì)胞重編程可由調(diào)控分化的基因完成,，并在此基礎(chǔ)上提出細(xì)胞命運(yùn)決定的“蹺蹺板模型”,。2013年5月23日,，該成果研究論文“Induction of pluripotency in mouse somatic cells with lineage specifiers”于《細(xì)胞》（Cell）期刊以封面文章形式在線發(fā)表?！都?xì)胞》同期還配發(fā)了希伯來大學(xué)Nissim Benvenisty教授對(duì)該工作的評(píng)論文章,。
2006年，日本科學(xué)家Shinya Yamanaka發(fā)現(xiàn)向小鼠體細(xì)胞轉(zhuǎn)入胚胎干細(xì)胞特異因子（OCT4, SOX2, KLF4, c-MYC）可以完成體細(xì)胞的重編程,。在此之后,，細(xì)胞重編程領(lǐng)域普遍認(rèn)為向目標(biāo)細(xì)胞狀態(tài)的轉(zhuǎn)變需要依賴于在目標(biāo)細(xì)胞中特異高表達(dá)的因子的誘導(dǎo)。因此目前發(fā)現(xiàn)的能在細(xì)胞重編程中發(fā)揮作用的因子均在胚胎干細(xì)胞中高表達(dá)并且與細(xì)胞干性維持緊密相關(guān),。
傳統(tǒng)觀點(diǎn)認(rèn)為分化因子與干性因子是相互拮抗,、相互抑制的。干性基因在胚胎干細(xì)胞中高表達(dá),，抑制分化基因,；分化基因在胚胎干細(xì)胞中不表達(dá)或低表達(dá)，高表達(dá)這些分化因子將抑制干性因子,，破壞胚胎干細(xì)胞多能性的狀態(tài),，導(dǎo)致其分化。
鄧宏魁研究組通過大規(guī)模篩選發(fā)現(xiàn),，細(xì)胞重編程中至關(guān)重要的干性因子OCT4能夠被調(diào)控中內(nèi)胚層（ME）發(fā)育和分化的因子（如GATA3,，GATA6，PAX1）代替,；SOX2能夠被調(diào)控外胚層（ECT）發(fā)育和分化的因子（如GMNN）代替,。湯超研究組根據(jù)這一發(fā)現(xiàn)創(chuàng)新性地建立了“蹺蹺板模型”，該模型可更好地理解中胚層基因和外胚層基因在重編程過程中相互抑制和相互平衡的關(guān)系,，這種關(guān)系可能決定了細(xì)胞命運(yùn)的維持和改變,。這一模型提供了誘導(dǎo)體細(xì)胞重編程的其它方法的預(yù)測(cè)，甚至還有一個(gè)出乎意料的模擬結(jié)果：如果同時(shí)過表達(dá)中內(nèi)胚層和外胚層基因,，就可以達(dá)到平衡從而同時(shí)替代SOX2和OCT4,。進(jìn)一步的實(shí)驗(yàn)結(jié)果也證實(shí)了這一可能，首次實(shí)現(xiàn)了用ME分化因子和ECT分化因子同時(shí)替代了細(xì)胞重編程過程中最關(guān)鍵的兩個(gè)干性因子OCT4和SOX2,。這一發(fā)現(xiàn)改變了向目標(biāo)細(xì)胞狀態(tài)的轉(zhuǎn)變需要由在目標(biāo)細(xì)胞中高表達(dá)的因子誘導(dǎo)的這一傳統(tǒng)觀點(diǎn),，為研究細(xì)胞命運(yùn)轉(zhuǎn)變提供了新視角,，為理解細(xì)胞重編程和細(xì)胞命運(yùn)決定的機(jī)制提供了新認(rèn)識(shí)。
鄧宏魁研究組的博士生舒健,、吳晨,、吳業(yè)濤與湯超研究組的博士生李志遠(yuǎn)為共同第一作者，鄧宏魁研究組的博士后趙揚(yáng)也在這一工作中發(fā)揮了關(guān)鍵作用,。（生物谷 Bioon.com）
圖1.“Seesaw模型”的landscape圖
圖2. 細(xì)胞命運(yùn)決定的“蹺蹺板模型”
生物谷推薦的英文摘要
Cell Doi：10.1016/j.cell.2013.05.001
Induction of pluripotency in mouse somatic cells with lineage specifiers
Jian Shu, Chen Wu, Yetao Wu, Zhiyuan Li, Sida Shao, Wenhui Zhao, Xing Tang, Huan Yang, Lijun Shen, Xiaohan Zuo, Weifeng Yang, Yan Shi, Xiaochun Chi, Hongquan Zhang, Ge Gao, Youmin Shu, Kehu Yuan, Weiwu He, Chao Tang, Yang Zhao, Hongkui Deng
The reprogramming factors that induce pluripotency have been identified primarily from embryonic stem cell (ESC)-enriched, pluripotency-associated factors. Here, we report that, during mouse somatic cell reprogramming, pluripotency can be induced with lineage specifiers that are pluripotency rivals to suppress ESC identity, most of which are not enriched in ESCs. We found that OCT4 and SOX2, the core regulators of pluripotency, can be replaced by lineage specifiers that are involved in mesendodermal (ME) specification and in ectodermal (ECT) specification, respectively. OCT4 and its substitutes attenuated the elevated expression of a group of ECT genes, whereas SOX2 and its substitutes curtailed a group of ME genes during reprogramming. Surprisingly, the two counteracting lineage specifiers can synergistically induce pluripotency in the absence of both OCT4 and SOX2. Our study suggests a “seesaw model” in which a balance that is established using pluripotency factors and/or counteracting lineage specifiers can facilitate reprogramming
